2-amino-4-cyclohexylamino-5-benzylpyrimidine



2-AMINO-4-CYCLOHEXYLAMINO-5- BENZYLPYRIMIDINE Aaron S. Goldberg, NewYork,

Chemical Co., Inc., New York i 1 Claim. (Cl. 260256.4)

N. Y., asslgnor to Nepera Yonkers, N. Y., a corporation of Thisinvention relates to, the preparation of certain novel pyrimidinecompounds and relates more particularly to the production of novel2-amino-4-substitutedamino-S-benzylpyrimidine compounds.

Compounds containing a pyrimidine nucleus are of wide pharmacologicinterest since compounds containing the basic pyrimidine structure areknown to play an important part in physiological processes. Compoundscontaining the pyrimidine structure are present in the cell nucleus inthe form of nucleoproteins. Vitamin B1, folic acid, and thymine areother important natural substances of pyrimidine structure. Although thestudy of the physiologically active pyrimidine compounds has occupiedthe attention of many investigators, the usefulness of many compoundswhich come within the broad class of pyrimidine compounds has, by nomeans, been fully determined since it is well known that relativelysmall changes in the structure of pyrimidine compounds have been foundto cause Widely diflferent physiological effects.

It is, therefore, an important object of my invention to provide certainnovel 2-arnino-4-substituted-amino-5-benzylpyrimidine compounds havingdesirable physiological activity.

Another object of this invention is the production of certain novelphysiologically active 2-amino-4-substitutedamino-S-benzylpyrimidinecompounds which may be obtained from available or readily synthesizedintermediates.

Other objects of this invention will appear from the following detaileddescription.

The novel pyrimidine compounds of my invention may be represented by thefollowing general formula GHQ wherein R is a substituted amino group.Thus, for example, R may be an alkylamino group, such as a methylamino,dimethylamino, ethylamino, diethylamino, dihydroxyethyl-amino,propylamino or other alkylamino group wherein the alkyl group containsup to about six carbon atoms or R may be a cycloalkyl amino group suchas a cyclohexylamino group. These compounds have an analeptic action.

The novel compounds of my invention may be prepared, for example, bycondensing ethyl hydrocinnamate:

with ethyl formate to obtain the intermediate compound ethyl a-formylhydrocinnamate United States Patent QCHIZHIEOCQHB H==O This intermediatemay then be reacted with gnanidine,

NH2-CNH:

in; to yield 2-amino-4-hydroxy-5-benzylpyrimidine.

GHQ s...

Example I 67 parts by weight of sodium metal and 2 parts by weight ofpotassium metal are placed in a reaction vessel, sufi'icient tolueneadded to cover the metal and the mixture then heated with some agitationuntil the sodium and potassium are melted. The toluent is then decantedfrom the molten alloy and a mixture of 375 parts by weight of ethylhydrocinnamate, 350 parts by weight of ethyl formate and 850 parts byweight of diethyl ether are gradually added to the sodium-potassiumalloy. The addition is made under reflux and at a rate suflicient tomaintain the exothermic reaction mixture at a lively boil. Hydrogen isgiven oil as a reaction product. When the addition of the ester mixtureis completed and the evolution of hydrogen ceases, the reaction mixtureis allowed to reflux for a period of about 1 hour. The mixture is pouredon to ice, the aqueous phase separated from the ether phase, and, afterwashing the ether phase once with dilute aqueous sodium hydroxide, theether phase is discarded. The aqueous sodium hydroxide phases arecombined, acidified with cold hydrochloric acid and the combinedacidified aqueous phase then extracted with ether. The ether layer isseparated andthe ether evaporated under reduced pressure. The formylester is then distilled under a pressure of 1 mm. or less. A yield of70% of theory of ethyla-formyl hydrocinnamate is obtained as theproduct.

25 parts by weight of gnanidine hydrochloride are dissolved in 66 partsby weight of 30% aqueous sodium hydroxide and the solution obtained isadded, with agitation, to 50 parts by weight of ethyl-a-formylhydrocinnamate. The temperature is maintained at about 60 C. for about30 minutes after which the temperature is raised to about C. Thetemperature is held at 85 C. for about one hour and the mixture thenheated to boiling at which temperature it is held for about one hour.The reaction mixture is cooled and partially neutralized withhydrochloric acid. The pH is finally brought to be between 7 and 8 bythe addition of acetic acid. The reaction mixture is then held at atemperature of 3 C. for 16 hours. The product formed is filtered otf,washed with cold water, then with some ether and finally with acetone. Ayield of 41% of theory of 2-amino-4-hydroxy-S-benzylpyrimidine isobtained, the crystalline product having a melting point of 240 C.

Example-II for two hours longer. The excess of phosphorus oxychlorideisremoved :under reduced pressure. The reaction mixture is diluted with40 parts by weight of cold chloroform and the diluted'reaction" mixturethen extracted about three times with ice water. The chloroform layer isthen diluted ,with about one-half of its volume of diethyl ether and anexcess of a saturatedaqueous' solution of sodium bicarbonate added; Theproduct precipitates out at the interface of the aqueous'and the organicphases. The product is separated, Washed. with Water and then withdiethyl ether. The 2-amino-4-chloro-5-benzylpyrimidine obtained isrecrystallized'from a mixture of chloroform-diethyl ether. A yield of60% of theory of 2 amino 4-chloro-5-benzylpyrimidine is obtained, theproduct melting at 183 C.

Examplelll' 3 parts byweight of 2-amino-4-chloro-5rbenzylpyrimia dineand 4 parts by weight of absolute ethyl alcohol. are heated in anautoclave at 100 C. for 10 hours with 8 parts by weight of a 33% byweight ethyl alcohol solution of dimethylamine- The autoclave is, openedand the reaction mixture reheated to about 70 C. Water is then added tocomplete precipitation and the entire mixture cooled. The crystalsformed are separated and washed with water. A yield of 84% of theory of2-amino-4-dimethylamino-5- benzylpyrimidine is obtained, the crystallineproduct meltingat185 C.

Example. I.V

To 1 part by weight of ,2-amino-4-chloro-S-benzylpyrirnidine is added2.5 parts by weight of absolute alcohol and 1.9 parts by weight ofcyclohexylamine and the reaction mixture heated in an-autoclave at 100C. for five hours. 10 parts by weight of diethyl ether are added to thereaction productrandrtheentire mixture then extracted about four timeswith water. The ether layer remaining is thenydried over, anhydroussodium sulfate andv concentrated byzremoving; a portiori;:-of the,ether. Petroleum ether is then added and crystallization of the productallowed to take place, by cooling the mixture at 3 C. for abouttwo'hours. 'A- yield of 90% of theory of 2'-amino-4- cyclohexylarnino 5benzylpyrimidine is obtained, the product meltingaa-t-a. temperatureofv132 C.

It is to be understood that the foregoing detailed description. is givenmerely by way of illustration and, that manyvariations may be'made'therein without departing from the spirit of my invention. 7

Having described my invention, ,what I desire to secure by.LettersPatent is: What I' claim is:'

2-amino-4-cyclohexylamino-S-benzylpyrimidine.

References Cited in the'file of this patent V UNITED STATESPATENTS2,649,449 Goldberg- "Aug. 18,1953 2;69.1-,-655- Hitchings: Get. 12, 1954OTHER REFERENCES Faleo et al.:,.Brit. I. Pharm'. and Chemotherapy, vol.6, pp. 188-95 (-1951). I

